This is a request for a Research Scientist Award for J. B. Justice, Jr., Professor of Chemistry, Emory University. The long term objective of this research is the understanding of the biological significance of the neurotransmitter dopamine (DA) in several structures in the central nervous system with respect to its role in drug abuse. Four areas of investigation are planned: 1) fundamental questions of in vivo measurement of neurotransmitters; 2) the neurochemistry of reward; 3) neurochemical effects of chronic cocaine; 4) individual differences in response to cocaine. Experiments are proposed which will test a new interpretation of in vivo microdialysis results and exploit these new findings to study the neurochemistry of drug abuse. It is essential to have a clear understanding of the data generated in microdialysis experiments to avoid misinterpretations as microdialysis is increasingly used in studies of drug abuse. The proposed fundamental studies apply to all transmitter systems, not just the dopaminergic system currently under investigation. In the second group of experiments, the relative importance of different DA pathways in cocaine abuse will be assessed using the self-administration paradigm. The aim of the present study is to reassess the relative contribution of several DA terminal fields and cell body regions in the reinforcing effects of cocaine. The particular methods used, that is local intracranial injection of cocaine during intravenous self-administration, will help to clarify the extent that structures other than the nucleus accumbens contribute to the reinforcing effects of cocaine. In the third group of experiments, the neurochemical perturbations caused by chronic cocaine administration will be assessed in vivo in DA systems using microdialysis and voltammetry. Alterations in synthesis, metabolism, release, uptake, and basal extracellular level will be determined in vivo as a function of time after chronic treatment. Individual differences in these processes with respect to response to cocaine will be assessed in the fourth group of experiments. The results of these experiments will help to guide future in vivo monitoring of neurochemical processes associated with abuse of drugs. A better understanding of the neurochemistry and neuroanatomy of drug induced reinforcement will help in developing approaches to treatment of drug abuse.